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SEMINAR ON DRY POWDER INHALERS PRESENTED BY N.RAJU

CONTENTS:

CONTENTS INTRODUCTION PHYSICO CHEMICAL PROPERTIES OF POWDER EMERGING TECHNOLOGIES FOR POWDER AEROSOL DELIVERY POWDER PRODUCTION AND FORMULATION DPI DEVICES TESTS TO ENSURE PRODUCT QUALITY ADVANTAGES AND DISADVANTAGES OF DRY POWDER INHALERS CONCLUSION REFERENCES

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DPIs are bolus drug delivery devices that contain solid drug, suspended or dissolved in a nonpolar volatile propellant or in a dry powder mix (DPI) that is fluidized when the patient inhales. But DPIs are complex in nature and their performance relies on many aspects including the design of inhaler, the powder formulation and the airflow generated by the patient. DPIs create aerosols by drawing air through a dose of dry powder medication. Unwanted systemic effects are minimised as the medication acts with maximum pulmonary specificity together with a rapid onset and duration of action. Performance of DPIs has improved significantly through the use of engineered drug particles and modified excipient systems. INTRODUCTION

PHYSICO CHEMICAL PROPERTIES OF POWDER:

PHYSICO CHEMICAL PROPERTIES OF POWDER Particle size Particle sizing techniques Moisture content and hygroscopicity Forces of interaction Fine particle fraction

EMERGING TECHNOLOGIES FOR POWDER AEROSOL DELIVERY:

EMERGING TECHNOLOGIES FOR POWDER AEROSOL DELIVERY The two main areas to be considered to improve inhalation drug delivery of powders are: (I) Powder production and formulation and (II) Dry Powder inhaler devices.

Powder Production and Formulation:

Powder Production and Formulation Freeze-drying Freeze-drying has been the process used to produce dry powders of proteins and peptides from a solution traditionally. Solution can be dried without being exposed to elevated temperatures, which may adversely affect the product stability. Powders prepared by this method are too large in size for inhalation. Milling of the freeze-dried powders to reduce particle size is feasible,the pressure, temperature, and shear resulting from milling may cause significant loss of bioactivity of proteins.

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Spray drying Spray drying involves converting the atomized liquid droplets into dry powders by hot air. The particle size and size distribution of the powder can be manipulated by the concentration of the feed solution, the spray temperature, cyclone efficiency, and chemical nature of the feed. Therapeutic proteins prepared as dry powders are found unstable when dried alone. Protein degradation can be minimized by cospray drying the protein with excipients.

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Molecular aggregation of recombinant human growth hormone (rhGH) due to air–liquid interfacial degradation can be prevented by adding polysorbate-20 or Zn 2+ into the liquid feed. Spray drying of recombinant humanized monoclonal antibody, anti-IgE (rhMAbE25) containing trehalose or lactose had ≤1% of aggregates formed following spray drying. In the case of follicle stimulating hormone (FSH), formulation containing mannitol, sucrose, and raffinose as excipients gave rise to ≤2% of the higher order aggregates formed from spray drying. These indicate that each protein/excipient system requires individual characterization to identify an optimal formulation for powder aerosol performance and protein stability.

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Spray Freeze-Drying Spray freeze-drying, a method developed for producing protein aerosol powders, involves spraying the solution into liquid nitrogen followed by freeze-drying. This process produces large(8 µ m–10 µ m) but porous particles of rhDNase and anti-IgE with high production yields (>95%). The fine particle fraction (FPF) of the spray freeze-dried powder was significantly higher than that of the spray dried powder due to improved aerodynamic properties . The process, is more costly, time consuming, and complex as compared with spray drying.

Process for Spray Drying Hydrophobic Drugs:

Process for Spray Drying Hydrophobic Drugs The conventional spray drying process is usually limited to hydrophilic drugs with hydrophilic excipients in aqueous solutions. It is not feasible for systems containing hydrophobic drugs and hydrophilic excipients or vice versa. A basic requirement is that the hydrophilic excipient and hydrophobic drug would be at least partially dissolved in the same organic solvent or cosolvent system. For example, both budesonide (hydrophobic drug) and povidone (hydrophilic excipient) have high solubility in methanol. Such a drug/excipient composition yielded powders of slightly dimpled spheres, with moisture content of 0.49 wt.%, and particle size of 2.3 µ m. The delivered dose efficiency was measured as ~ 50 wt.%.

Solvent precipitation:

Solvent precipitation The solvent precipitation method utilizes the unique properties of nonsolvent at a critical temperature and pressure to precipitate solid particles of drugs from solutions. Carbon dioxide, which exhibits remarkable solvent power at its critical temperature of 31.1 o C and pressure of 70 bar for high molecular weight and low vapor pressure solids, is an ideal nonsolvent choice. CO 2 is also nontoxic, inexpensive, and readily available. York and Hanna have developed the SEDS (solution enhanced dispersion by supercritical fluids) process for preparing powders of anti-asthmatic drugs. Alternatively, protein particles can be produced using a supercritical or near critical CO 2 -assisted aerosolization and bubble drying process. Recently, Bustami have investigated the feasibility of the ASES (aerosol solvent extraction system) process to generate microparticles of proteins for inhalation.

Ways to improve powder flowability and dispersability:

Ways to improve powder flowability and dispersability Inclusion of Excipient Powders prepared by any one of the above methods may not be used directly as the powders may be too cohesive for device filling and for administration as an aerosol. In contrast to the traditional approach of using binary blend systems (i.e., drug plus coarse carrier), the addition of fine carrier particles (<10 µm) such as lactose and magnesium stearate to form a ternary system has been shown to further enhance the amount of drug particles in the aerosol cloud. Recently, Ganderton, Morton, and Lucas have found that the inclusion of low-density amino acid particles produced by spray drying can also enhance the amount of fine particles in the aerosol. Another conventional approach to improving powder flow and dispersion is to form agglomerates

Tailor-made powders:

Tailor-made powders Fig. 1 AIR TM particle. Prepared by spray drying solutions containing a mixture of drug and biodegradable material. Have a low tapped density of less than 0.4 g/cm 3 with an irregular surface. These low-density particles are physically large but aerodynamically small, which enhances the flow and dispersion of powders, and are ideal for deep lung delivery. AIR TM Particles

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Pulmosphere TM hollow and porous bulk density of 0.05 g/cm3–0.2 g/cm 3 Size between 2 µ m and 4 µ m. Wrinkled Surface Particles Hollow and porous, solid protein particles with wrinkled surfaces The reduction of the surface contacts among the wrinkle particles is believed to reduce powder cohesion. Wrinkled bovine serum albumin particles

DPI DEVICES:

DPI DEVICES The performance of the DPI system depends not only on the powder formulation but also on the inhaler device. Recent inventions of the powder inhaler device are aimed at improving the inhaler’s dispersion efficiency and reducing the resistance of the device as well as decoupling powder dispersion from the patient’s inspiratory effort in order to deliver accurate and flexible dosages for different patient’s needs. The internal geometry of the DPI device influences the resistance to inspiration and the inspiratory flow required to deaggregate and aerosolize the medication. Devices with higher resistance require a higher inspiratory flow to produce a dose. Inhalation through a high-resistance DPI may provide better drug delivery to the lower respiratory tract.

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Principle of dry powder inhaler design . The formulation typically consists of micronized drug blended with larger carrier particles, dispensed by a metering system. An active or passive dispersion system entrains the particles into the patient’s airways, where drug particles separate from the carrier particles and are carried into the lung.

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Classification of DPI devices Single-unit dose devices Eg: Spinhaler ,Rotahaler ,Handihaler Multi-dose reservoir devices Eg: Turbuhaler, Easyhaler, Twisthahaler Multi-unit dose devices Eg: Aerohaler, Diskhaler

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Single-unit dose devices Spinhaler™ In the Spinhaler™, the capsule is placed into a holder located on top of a propeller. The walls of the capsule are pierced by two spears when the patient primes the device by sliding a cam. Spinhaler™,

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Rotahaler™ In the Rotahaler™ the capsule is severed by a twisting action. Once the capsule has been broken, the patient inhales through the device causing the propeller to turn and vibrate dispersing the powder into the inspired airstream. After use, the remains of the gelatin capsule must be removed from the inhaler before the next capsule can be placed in the device. Rotahaler™

InnovaTM:

Innova TM InnovaTM unit dose inhaler that has been designed for long-term use have the capability to fluidize and extract up to 90% of the dose from the reservoir.

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Multi-dose reservoir devices Multi-dose reservoir devices contain a bulk supply of drug from which individual doses are released with each actuation. The first such inhaler to be developed was the Turbuhaler™. Other multi-dose reservoir devices have become available in recent years including the Easyhaler™ ,Clickhaler™, and Twisthaler™ . Turbuhaler™. Twisthaler™ .

Multi-unit dose devices :

Multi-unit dose devices Multi-unit dose DPIs utilise individually prepared and sealed doses of drug. The first such DPI was the Aerohaler™ which contained six unit dose capsules each delivering one dose of drug. Aerohaler™

(A) Hovione SA FlowCaps dry powder device. (B) Photograph showing the dispersion of powders within the capsule in a Hovione SA FlowCaps dry powder inhaler.:

(A) Hovione SA FlowCaps dry powder device. (B) Photograph showing the dispersion of powders within the capsule in a Hovione SA FlowCaps dry powder inhaler.

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Examples of complex tests necessary to ensure product quality: Particle size distribution Moisture content Leak rate Leachables Microbial limits

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Particle size distribution - Cascade impactor More critical for MDIs and DPIs Change in PSD Decrease in efficacy Increase in systemic exposure Inability to meet particle size distribution specifications has resulted in product recalls

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Moisture Content Most critical for MDI suspension formulations and for DPIs Strict limits needed to prevent changes Particle size distribution Crystal growth and aggregation Leak Rate Influences performance of actuator and valve Delivery of the proper dose to the patient Leakage may influence formulation composition Change particle size distribution and/or dose content uniformity Failure to meet specifications

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Leachables Requires identification and quantitation Concentration profile established Make evident undisclosed changes Microbial Limits Total aerobic count Total yeast and mold count Freedom from pathogens Additional testing is necessary for product development Ensure formulation does not support microbial growth Microbial quality is maintained throughout the expiration dating period

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Advantages of the Dry Powder Inhaler Environmental sustainability, propellant-free design Little or no patient coordination required Formulation stability Disadvantages of the Dry Powder Inhaler Deposition efficiency dependent on patient’s inspiratory airflow Potential for dose uniformity problems Development and manufacture more complex/expensive

CONCLUSION:

CONCLUSION DPIs have several advantages in delivering drugs to the lungs, including targeted delivery, which can improve efficacy and reduce unwanted systemic side effects, a large surface area for absorption, rapid absorption, absence of first-pass metabolism, rapid onset of action and high bioavailabity. Interest in DPIs has increased in the last decade, in response to the need for alternatives to propellant-driven devices and new approaches to the delivery of potent new chemical entities of biological origin. The ‘ideal’ dry powder inhaler is the one that delivers consistent and reliable doses and is the one that the patient trusts, finds easy to use and prefers over others. There is no single ‘ideal’ DPI that fulfils all those criteria for the entire spectrum of patients who use inhaled medications, the evidence suggests that multi-unit dose DPIs such as Diskus™ offer the most reliable and consistent pharmaceutical performance, and are preferred by patients who rate them as the easiest to use. .

REFERENCES:

REFERENCES Patton, J.S.; Bukar, J.; Nagarajan, S. Inhaled insulin. Adv.Drug Deliv. Rev. 1999, 35, 235–247. Clark, A.; Foulds, G.H. Aerosolized Active Agent Delivery.World IPO 9,947,196, 1999. Platz, R.M.; Ip, A.; Whitham, C.L. Process for PreparingMicronized Polypeptide Drugs. US patent 5,354,562, , 1994. Platz, R.M.; Utsumi, J; Satoh, Y; Naruse, N PharmaceuticalAerosol Formulation of Solid Formulation of Solid Polypeptide Microparticles and Method for the Preparation Thereof. World IPO 9,116,038, 1991. Vidgren, M.T.; Vidgren, P.A.; Paronen, T.P. Comparison of physical and inhalation properties of spray dried and mechanically micronized disodium cromoglycate. Int. J.Pharm. 1997, 35, 139–144. Masters, K. Spray Drying Handbook; John Wiley & Sons:New York, 1976.

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Frijlink HW, Boer AD. Dry powder inhalers for pulmonary drug delivery. Expert Opion in Drug Delivery 2004; 1(1): 67-86. Chan HK. Dry powder aerosol delivery systems: current and future research directions. J Aerosol Med 2006; 19 (1): 21-27. Ashurst S, Malton A, Prime D, Pstt BS. Latest advances in the developmentof dry powder inhaler. Pharm Sci Technol Today 2000; 3(7): 246-256. Patton JS , Bukar J, Nagarajan S. Inhaled insulin. Adv Drug del Rev 1999; 35: 235-247. Maa YF, Prestrelski SJ. Biopharmaceutical powders: particle formation and formulation considerations. Current Pharm Biotech 2000; 1(283-302) 1389-2010.

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Di L, Kerns EH. Profiling drug-like properties in discovery research.Curr Opin Chem Biol 2003;7(3):402–408. Chan, H.-K.; Clark, A.; Gonda, I.; Mumenthaler, M.; Hsu,C. Spray dried powders and powder blends of recombinant human deoxyribonuclease (rhDNase) for aerosol delivery.Pharm. Res. 1997, 14, 431–497. Freedman T. Medihaler therapy for bronchial asthma: a new type of aerosol therapy. Postgrad Med J. 1956;20:667–73. Brompton Hospital/MRC Collaborative trial. Double-blind trial comparing two dosage schedules of beclomethasone dipropionate aerosol in the treatment of chronic bronchial asthma. Lancet. 1974;2:303–7. [PubMed] Bell JH. Dry powder aerosols 1: a new powder inhalation device. J Pharm Sci. 1971;10:1559–64. [PubMed]

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